Psoriasis affects over 7 million people in the US (125 million people worldwide) and is the most common helper T-cell (Th)-1, Th-17 mediated inflammatory disease in humans. Epidemiological studies indicate that psoriasis is associated with an increased risk for major cardiovascular (CV) events and premature death due to CV disease independent of traditional risk factors. It is not know if successful treatment of psoriasis modulates CV risk. Furthermore, treatment of psoriasis and other inflammatory disease states with tumor necrosis factor alpha inhibitors (TNF-I s) has reached over 1 million people and there are observational studies demonstrating modulation of lipoproteins and CV risk with these drugs, however, a randomized trial of these endpoints is necessary to confirm these findings. Given that inflammation is an important pathogenic process in cardiometabolic disease, reduction of inflammation systemically by treating psoriasis provides a human, in vivo model to understand the link between modulation of chronic inflammation and CV disease in a population where treatment of the disease is elective providing an ethical placebo arm. The recent development of 18[F]-2-fluoro-2-deoxy-D-glucose (FDG) imaging using positron-emission tomography (PET)/computed tomography (CT) for measuring vascular inflammation provides a modality to test this hypothesis in vivo. Furthermore, FDG PET CT addresses a critical barrier to progress in the field as it allows for dynamic in vivo measurement of vascular inflammation in a manner which is highly sensitive, reproducible, modifiable over a short term following intervention, and predictive of clinically important CV events. We have assembled highly skilled, diverse collaborators who are leaders in psoriasis cardiovascular research, PET/CT vascular imaging, lipoprotein metabolism and cardiovascular translational focused on inflammatory patho-mechanisms of metabolic and atherosclerotic disease. This team provides a significant opportunity to address the interdisciplinary nature of the problem of studying the interrelationship of two common, but phenotypically distinct diseases. We therefore propose a randomized, placebo controlled trial to determine if treatment of psoriasis improves vascular inflammation measured by FDG PET CT and cardiometabolic disease measured by known CV biomarkers (including dyslipidemia, HDL function, metabolic, and inflammatory-based measures) using three treatment arms: systemic immunomodulation with TNF-I s; skin-directed therapy with ultraviolet B (UVB) phototherapy; and placebo. Through the studies proposed, we will improve scientific understanding of how treatment with TNF-I s and UVB phototherapy modulate vascular inflammation and cardiometabolic disease in vivo and ex vivo compared to placebo. These results will be a critical step in determining how treatment of psoriasis affects CV risk in this vulnerable patient population and will concurrently improve scientific knowledge of off target effects of the commonly used TNF-I s. PUBLIC HEALTH RELEVANCE: The proposed project will determine how therapies commonly used for psoriasis and other inflammatory diseases impact vascular inflammation and blood markers of cardiovascular risk. This research will help determine if treating psoriasis may lower the risk of major cardiovascular problems and will have broad implications for our understanding of how suppressing inflammation affects lipid metabolism and cardiovascular disease.